High‐level expression of a human immunoglobulin γ1 transgene depends on switch region sequences

Gram, Hermann; Zenke, Gerhard; Geisse, Sabine; Kleuser, Beate; Bürki, Kurt

doi:10.1002/eji.1830220512

Cited by 21 publications

(15 citation statements)

References 58 publications

(29 reference statements)

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“…The differences between IL-4 and IL-10 could reflect a differential transcription activation at the switch region locus. Indeed, switch regions have been reported to play a critical role in the upregulation of IgH gene expression in vivo, most likely at the transcriptional level (35). In conclusion, in humans, IL-4 and IL-13 are responsible for the induction of isotype switching towards IgE and IgG (13)(14)(15)36), TGF-J~ for IgA (11), and IL-10 for IgG1 and IgG3 (16).…”

Section: Discussionmentioning

confidence: 91%

Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes.

Malisan¹,

Brière²,

Bridon³

et al. 1996

The Journal of Experimental Medicine

159

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SummaryUpon activation, B lymphocytes can change the isotype of the antibody they express by immunoglobulin (Ig) isotype switch recombination. In previous studies on the regulation of human IgG expression, we demonstrated that interleukin 10 (IL-10) could stimulate IgG1 and IgG3 secretion by human CD40-activated naive (slgD +) tonsillar B cells. To assess whether IL-10 actually promotes the DNA recombination underlying switching to these isotypes, we examined the effect of IL-10 on the generation of reciprocal products that form DNA circles as byproducts of switch recombination. The content of reciprocal products characteristic of p.-~/recombination was elevated after culture of CD40-activated tonsillar slgD + B cells with either IL-4 or IL-10, although high levels of IgG secretion were observed only with IL-10. Unlike IL-4, IL-10 did not induce reciprocal products of p~-e and ~/-e switch recombination. These results demonstrate that IL-10 promotes both switching to ",/and IgG secretion.

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Section: Discussionmentioning

confidence: 91%

Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes.

Malisan¹,

Brière²,

Bridon³

et al. 1996

The Journal of Experimental Medicine

159

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“…Although the switch region is required for high-level expression of IgH-derived transgenes (15,40), the switch-associated elements are not important for expression of the endogenous gene in our hybridoma cell lines (31). The recombinants analyzed here bear deletions which were designed to test the importance in transcription of the MARs and the E enhancer.…”

Section: Discussionmentioning

confidence: 99%

Expression of the (Recombinant) Endogenous Immunoglobulin Heavy-Chain Locus Requires the Intronic Matrix Attachment Regions

Oancea

Berrú

Shulman

1997

Molecular and Cellular Biology

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The elements which regulate gene expression have traditionally been identified by their effects on reporter genes which have been transfected into cell lines or animals. It is generally assumed that these elements have a comparable role in expression of the corresponding endogenous locus. Nevertheless, several studies of immunoglobulin heavy-chain (IgH) gene expression have reported that the requirements for expressing IgH-derived transgenes differ from the requirements for expression of the endogenous IgH locus. Thus, although expression of transgenes requires multiple elements from the J H -C intron-the E core enhancer, the matrix attachment regions (MARs) which flank E, and several switch-associated elements-B-cell lines in which expression of the endogenous heavy-chain gene is maintained at the normal level in the absence of these intronic elements have occasionally been reported. Gene targeting offers an alternative method for assessing regulatory elements, one in which the role of defined segments of endogenous genes can be evaluated in situ. We have applied this approach to the IgH locus of a hybridoma cell line, generating recombinants which bear predetermined modifications in the functional, endogenous heavy-chain gene. Our analysis indicates the following. Chromatin fibers appear to exist as loops which are anchored to the nuclear matrix, or scaffold (reviewed in reference 25). The loops are thought to correspond to functional domains in which the transcriptional state of one domain is largely independent of its neighbors. It is generally considered that the sites of anchorage in the DNA have a particular affinity for the matrix and can therefore be identified as matrix attachment regions (MARs) or scaffold attachment regions.As illustrated in Fig.

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“…These variables can be separated, in principle, by constructing transgenic mice in which IgG or another downstream isotype is constitutively expressed as the sole BCR on B cells independent of any need for immunization. A number of research groups have constructed IgG-transgenic mice with different V H /V L specificities, but these have yielded variable results and conclusions (23)(24)(25)(26)(27)(28)(29)(30). In some studies, the ␥ heavy chain (Hc) signaled allelic exclusion, at least to the extent that endogenous IgM expression was inhibited in the bone marrow (27,28,30,31), whereas in other studies allelic exclusion was not apparent (23,24).…”

Section: Introductionmentioning

confidence: 99%

Gene Dose–Dependent Maturation and Receptor Editing of B Cells Expressing Immunoglobulin (Ig)g1 or Igm/Igg1 Tail Antigen Receptors

Pogue

Goodnow

2000

The Journal of Experimental Medicine

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Conserved differences between the transmembrane and cytoplasmic domains of membrane immunoglobulin (Ig)M and IgG may alter the function of antigen receptors on naive versus memory B cells. Here, we compare the ability of these domains to signal B cell allelic exclusion and maturation in transgenic mice. A lysozyme-binding antibody was expressed in parallel sets of mice as IgM, IgG1, or a chimeric receptor with IgM extracellular domains and transmembrane/cytoplasmic domains of IgG1. Like IgM, the IgG1 or chimeric IgM/G receptors triggered heavy chain allelic exclusion and supported development of mature CD21+ B cells. Many of the IgG or IgM/G B cells became CD21high and downregulated their IgG and IgM/G receptors spontaneously, resembling memory B cells and B cells with mutations that exaggerate B cell antigen receptor signaling. Unlike IgM-transgenic mice, “edited” B cells that carry non–hen egg lysozyme binding receptors preferentially accumulated in IgG and IgM/G mice. This was most extreme in lines with the highest transgene copy number and diminished in variant offspring with fewer copies. The sensitivity of B cell maturation to transgene copy number conferred by the IgG transmembrane and cytoplasmic domains may explain the diverse phenotypes found in other IgG-transgenic mouse strains and may reflect exaggerated signaling.

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High‐level expression of a human immunoglobulin γ1 transgene depends on switch region sequences

Cited by 21 publications

References 58 publications

Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes.

Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes.

Expression of the (Recombinant) Endogenous Immunoglobulin Heavy-Chain Locus Requires the Intronic Matrix Attachment Regions

Gene Dose–Dependent Maturation and Receptor Editing of B Cells Expressing Immunoglobulin (Ig)g1 or Igm/Igg1 Tail Antigen Receptors

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